Pulmonary interstitial pressure and tissue matrix structure in acute hypoxia.
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Pulmonary interstitial pressure was measured via micropuncture in anesthetized rabbits in normoxia and after breathing 12% O(2). In normoxia [arterial PO(2) = 88 +/- 2 (SD) mmHg], pulmonary arterial pressure and pulmonary interstitial pressure were 16 +/- 8 and -9.6 +/- 2 cmH(2)O, respectively. After 6 h of hypoxia (arterial PO(2) = 39 +/- 16 mm Hg), the corresponding values were 30+/-8 and 3.5+/-2.5 cm H(2)O (P<0.05). Pulmonary interstitial proteoglycan extractability, evaluated by hexuronate assay after 0.4 M guanidinium hydrochloride extraction, was 12.3, 32.4, and 60.6 microg/g wet tissue in normoxia and after 3 and 6 h of hypoxia, respectively, indicating a weakening of the noncovalent bonds linking proteoglycans to other extracellular matrix components. Gel filtration chromatography showed an increased fragmentation of chondroitin sulfate- and heparan sulfate-proteoglycans during hypoxic exposure, accounting for a loss of extracellular matrix native architecture and basement membrane structure. Gelatin zymography demonstrated increased amounts of the proteolytically activated form of gelatinase B (matrix metalloproteinase-9) after hypoxic exposure, providing evidence that the activation of proteinases may play a role in hypoxia-induced lung injury. (+info)
Effect of pulmonary stretch receptor feedback and CO(2) on upper airway and respiratory pump muscle activity in the rat.
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1. Our purpose was to examine the effects of chemoreceptor stimulation and lung inflation on neural drive to tongue protrudor and retractor muscles in the rat. 2. Inspiratory flow, tidal volume, transpulmonary pressure, compliance and electromyographic (EMG) activity of genioglossus (GG), hyoglossus (HG) and inspiratory intercostal (IIC) muscles were studied in 11 anaesthetized, tracheotomized and spontaneously breathing rats. Mean EMG activity during inspiration was compared with mean EMG activity during an occluded inspiration, at each of five levels of inspired CO(2) (0, 3, 6, 9 and 12 %). 3. Lung inflation suppressed EMG activity in all muscles, with the effect on both tongue muscles exceeding that of the intercostal muscles. Static elevations of end-expiratory lung volume evoked by 2 cmH(2)O positive end-expiratory pressure (PEEP) had no effect on tongue muscle activity. 4. Despite increasing inspiratory flow, tidal volume and transpulmonary pressure, the inhibition of tongue muscle activity by lung inflation diminished as arterial PCO2 (P(a),CO(2)) increased. 5. The onset of tongue muscle activity relative to the onset of IIC muscle activity advanced with increases in P(a),CO(2) but was unaffected by lung inflation. This suggests that hypoglossal and external intercostal motoneuron pools are controlled by different circuits or have different sensitivities to CO(2), lung inflation and/or anaesthetic agents. 6. We conclude that hypoglossal motoneuronal activity is more strongly influenced by chemoreceptor-mediated facilitation than by lung volume-mediated inhibition. Hypoglossal motoneurons driving tongue protrudor and retractor muscles respond identically to these stimuli. (+info)
Contribution of spindle reflexes to post-inspiratory activity in the canine external intercostal muscles.
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1. The external intercostal muscles have greater post-inspiratory activity than the parasternal intercostal muscles and are more abundantly supplied with muscle spindles. In the present study, the hypothesis was tested that spindle afferent inputs play a major role in determining this activity. 2. The electrical activity of the external and parasternal intercostal muscles in the rostral interspaces was recorded in anaesthetized spontaneously breathing dogs, and the ribs were manipulated so as to alter their normal caudal displacement and the normal lengthening of the muscles in early expiration. 3. Post-inspiratory activity in the external intercostal muscles showed a reflex decrease when the caudal motion of the ribs and the lengthening of the muscles was impeded, and it showed a reflex increase when the rate of caudal rib motion and muscle lengthening was increased. In contrast, the small post-inspiratory activity in the parasternal intercostal muscles remained unchanged. 4. When the two ribs making up the interspace investigated were locked to keep muscle length constant, post-inspiratory activity in the external intercostal muscles was reduced and no longer responded to cranial rib manipulation. 5. These observations confirm that afferent inputs from muscle receptors, presumably muscle spindles, are a primary determinant of post-inspiratory activity in the canine external intercostal muscles. In anaesthetized animals, the contribution of central control mechanisms to this activity is small. (+info)
PKA, PKC, and AKAP localization in and around the neuromuscular junction.
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BACKGROUND: One mechanism that directs the action of the second messengers, cAMP and diacylglycerol, is the compartmentalization of protein kinase A (PKA) and protein kinase C (PKC). A-kinase anchoring proteins (AKAPs) can recruit both enzymes to specific subcellular locations via interactions with the various isoforms of each family of kinases. We found previously that a new class of AKAPs, dual-specific AKAPs, denoted D-AKAP1 and D-AKAP2, bind to RIalpha in addition to the RII subunits. RESULTS: Immunohistochemistry and confocal microscopy were used here to determine that D-AKAP1 colocalizes with RIalpha at the postsynaptic membrane of the vertebrate neuromuscular junction (NMJ) and the adjacent muscle, but not in the presynaptic region. The labeling pattern for RIalpha and D-AKAP1 overlapped with mitochondrial staining in the muscle fibers, consistent with our previous work showing D-AKAP1 association with mitochondria in cultured cells. The immunoreactivity of D-AKAP2 was distinct from that of D-AKAP1. We also report here that even though the PKA type II subunits (RIIalpha and RIIbeta) are localized at the NMJ, their patterns are distinctive and differ from the other R and D-AKAP patterns examined. PKCbeta appeared to colocalize with the AKAP, gravin, at the postsynaptic membrane. CONCLUSIONS: The kinases and AKAPs investigated have distinct patterns of colocalization, which suggest a complex arrangement of signaling micro-environments. Because the labeling patterns for RIalpha and D-AKAP 1 are similar in the muscle fibers and at the postsynaptic membrane, it may be that this AKAP anchors RIalpha in these regions. Likewise, gravin may be an anchor of PKCbeta at the NMJ. (+info)
On the respiratory function of the ribs.
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To assess the respiratory function of the ribs, we measured the changes in airway opening pressure (Pao) induced by stimulation of the parasternal and external intercostal muscles in anesthetized dogs, first before and then after the bony ribs were removed from both sides of the chest. Stimulating either set of muscles with the rib cage intact elicited a fall in Pao in all animals. After removal of the ribs, however, the fall in Pao produced by the parasternal intercostals was reduced by 60% and the fall produced by the external intercostals was eliminated. The normal outward curvature of the rib cage was also abolished in this condition, and when the curvature was restored by a small inflation, external intercostal stimulation consistently elicited a rise rather than a fall in Pao. These findings thus confirm that the ribs play a critical role in the act of breathing by converting intercostal muscle shortening into lung volume expansion. In addition, they carry the compression that is required to balance the pressure difference across the chest wall. (+info)
Coupling between the ribs and the lung in dogs.
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In contrast to the conventional theory, the external and internal intercostal muscles show marked rostrocaudal gradients in their actions on the lung. We hypothesized that these gradients are the result of a non-uniform coupling between the ribs and the lung. Rib displacements (X(r)) and the changes in airway opening pressure (P(a,o)) were thus measured in anaesthetized, pancuronium-treated, supine dogs while loads were applied in the cranial direction to individual pairs of odd-numbered ribs and in the caudal direction to individual pairs of even-numbered ribs. During cranial loading, X(r) induced by a given load increased gradually with increasing rib number. The decrease in P(a,o) also increased from the third to the fifth rib pair but then decreased markedly to the eleventh pair. A similar pattern was observed during caudal loading, although X(r) and DeltaP(a,o) were smaller. These results were then combined to calculate the net X(r) and the net DeltaP(a,o) that a hypothetical intercostal muscle lying parallel to the longitudinal body axis would produce in different interspaces. The net X(r) was cranial in all interspaces. However, whereas the net DeltaP(a,o) was negative in the cranial interspaces, it was positive in the caudal interspaces. These observations confirm that the coupling between the ribs and the lung varies from the top to the base of the ribcage. This coupling confers to both the external and the internal intercostal muscles an inspiratory action on the lung in the cranial interspaces and an expiratory action in the caudal interspaces. (+info)
Effect of chest wall vibration on the canine diaphragm during breathing.
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High-frequency mechanical vibration of the ribcage reduces dyspnoea in patients with chronic obstructive pulmonary disease, and the suggestion has been made that this effect might be related to a decrease in central respiratory drive resulting from an increase in afferent inputs from intercostal muscles. In the present studies, the effects of ribcage vibration on central respiratory drive have been assessed without the confounding influence of conscious reactions. The electromyographic (EMG) activity of the diaphragm and the changes in pleural (Ppl) and abdominal (Pab) pressure were measured in six anaesthetized, spontaneously-breathing dogs while the rostral, the middle, or the caudal portion of the ribcage was vibrated at intervals during inspiration. The EMG activity of the external and parasternal intercostals was also measured. Ribcage vibration consistently elicited a marked increase in the inspiratory EMG activity recorded from the external intercostals, thus indicating that the procedure did activate intercostal muscle spindles. However, no alteration in diaphragmatic or parasternal intercostal EMG activity was seen in any animal. Transdiaphragmatic pressure and the relationship between deltaPab and deltaPpl during inspiration were also unaltered. The authors conclude that ribcage vibration and, with it, stimulation of external intercostal muscle spindles has no significant influence on phrenic motoneurones or on medullary inspiratory neurones. It is unlikely, therefore, that the beneficial effect of the procedure on dyspnoea results from a specific reduction in central respiratory drive. (+info)
Respiratory muscle dynamics and control during exercise with externally imposed expiratory flow limitation.
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To determine how decreasing velocity of shortening (U) of expiratory muscles affects breathing during exercise, six normal men performed incremental exercise with externally imposed expiratory flow limitation (EFLe) at approximately 1 l/s. We measured volumes of chest wall, lung- and diaphragm-apposed rib cage (Vrc,p and Vrc,a, respectively), and abdomen (Vab) by optoelectronic plethysmography; esophageal, gastric, and transdiaphragmatic pressures (Pdi); and end-tidal CO2 concentration. From these, we calculated velocity of shortening and power (W) of diaphragm, rib cage, and abdominal muscles (di, rcm, ab, respectively). EFLe forced a decrease in Uab, which increased Pab and which lasted well into inspiration. This imposed a load, overcome by preinspiratory diaphragm contraction. Udi and inspiratory Urcm increased, reducing their ability to generate pressure. Pdi, Prcm, and Wab increased, indicating an increased central drive to all muscle groups secondary to hypercapnia, which developed in all subjects. These results suggest a vicious cycle in which EFLe decreases Uab, increasing Pab and exacerbating the hypercapnia, which increases central drive increasing Pab even more, leading to further CO2 retention, and so forth. (+info)